Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- Number of Participants With Adverse Events Related to AVI-4568
研究概览
简要总结
Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disorder, arises from mutations in the dystrophin gene. Antisense therapy with the use of antisense oligonucleotides (AON) has the potential to restore effectively the production of dystrophin, the defective protein, in >70% of DMD. This could result in increased life expectancy through improved muscle survival and function. Recent scientific research has demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. Having demonstrated proof-of-principle in human cell culture and animal model studies, we now intend to determine efficacy and safety of this approach to induce dystrophin exon skipping in children with DMD.
The specific aim of this phase I/II study is to assess efficacy (dystrophin production) and safety of intramuscular administered morpholino oligomer directed against exon 51 (AVI-4658 PMO). We are performing parallel preclinical studies to develop methods of systemic delivery that will be necessary for future phase II/III clinical studies.
详细描述
Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy affecting 1 in every 3500 live male births. The disease is characterised by severe muscle wasting and weakness, which becomes clinically evident between the ages of 3 to 5 years. Affected individuals stop walking by 12 years of age and usually do not survive beyond the age of 20 unless ventilated. In general DMD is caused by mutations that disrupt the reading frame thus leading to a failure to express dystrophin.
Recent scientific research has led to the belief that DMD may be treated by correcting the genetic error in the dystrophin gene which causes DMD. Most children with DMD have a deletion, i.e., a mutation which removes part of the dystrophin gene. A novel technique using antisense technology to skip a specific exon and bypass faulty genetic material, thus allowing production of functional dystrophin to be produced, has been developed.These antisense oligonucleotides (AON) target and bypass faulty genetic material and allow production of functional protein.This has been successfully demonstrated in cultured human DMD cells and in mouse and canine DMD models.The restored production of dystrophin is predicted to reduce muscle pathology significantly.
In the early part of the study we compared different antisense oligomers chemical modification and concluded that the morpholino backbone is significantly superior when administered to skeletal muscle compared to a number of other types of antisense.
The aim of this phase I/II clinical study is to assess efficacy and safety of AVI-4658, a morpholino antisense directed against exon 51, in DMD individuals with deletions which would benefit from skipping exon 51.
The proposed work is presented in 4 sections detailing the main approaches.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 10 Years 至 17 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Subject is male ≥ 10 years and ≤ 17 years of age at the time of study drug administration.
- •Subject has clinical diagnosis compatible with Duchenne's Muscular Dystrophy (DMD) and evidence of mutational and dystrophin defects from muscle biopsy consistent with DMD (out-of frame deletions, absent dystrophin).Eligible deletions are those that can be rescued by the skipping of exon 51 [45-50; 47-50; 48-50; 49-50; 50; 52; 52-63].
- •Subject has had a muscle biopsy analysed, showing <5% revertant fibres present. Biopsy may be collected at the time of DMD diagnosis or as part of protocol screening procedures.
- •Subject is unable to ambulate or stand independently.
- •Subject has Stage 1 to 3 EDB muscle preservation determined by MRI.
- •Subject has a forced vital capacity ≥ 25% confirmed within 3 months from Day One.
- •Subject has mean oxygen saturation monitoring > 94% in overnight domiciliary overnight sleep study within 3 months of Day One.
- •Subject has the ability to comply with all study evaluations and return for all study.
- •Subject and parent have psychiatric adjustments, adequately supportive psychosocial circumstances and a full understanding of study aims process and likely outcomes.
排除标准
- •Subject has had external digitorum brevis (EDB) muscle removed.
- •Subject has Stage 4 EDB muscle preservation determined by MRI.
- •Subject has a left ventricular shortening fraction of < 25% and/or an ejection fraction of < 35% by echocardiography at visit one or within three months of visit one.
- •Subject has evidence of nocturnal hypoventilation (mean oxygen saturation at night of ≤ 94%) confirmed via overnight sleep study at Visit One (as screening procedure) or within 3 months of Visit One by overnight sleep study.
- •Subject has severe respiratory insufficiency defined by the need for invasive or non-invasive mechanical ventilation (does not include nocturnal ventilatory support).
- •Subject has severe cognitive dysfunction rendering them unable to understand and collaborate with study protocol.
- •Subject has immune deficiency or autoimmune disease.
- •Subject has a known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
- •Subject has received pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz.,anabolic steroids, creatine protein supplementation, albuterol or other beta agonists).
- •Subject has had surgery within 3 months of study entry or planned for anytime during study.
- •Subject has active significant illness at time of study entry.
- •Subject has is unable to undergo MRI testing (viz., has metal implants).
- •Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances, recent significant emotional loss, history of depressive or anxiety disorders that might interfere with protocol completion or compliance.
- •Subject has any known allergies to products likely to be used in the study (viz.,antiseptics, anaesthetics).
- •Subject has used any experimental treatments or has participated in any clinical trial within 4 weeks of study entry.
- •Subject has used intranasal, inhaled or topical steroids for a condition other than muscular dystrophy within 1 weeks of study entry.
研究组 & 干预措施
High dose
High dose of AVI-4658
干预措施: AVI-4658 (PMO) (Drug)
Low dose
Low dose of AVI-4658
干预措施: AVI-4658 (PMO) (Drug)
结局指标
主要结局
Number of Participants With Adverse Events Related to AVI-4568
时间窗: Baseline up to Day 120
Number of Subjects with Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Number of Participants With Injection Site Reactions
时间窗: From the Day of Screening to Day 3
Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values
时间窗: From the Day of Screening up to Day 28
Assessed by light microscopy and immunocytochemistry to detect the differences in inflammatory infiltrates between the AVI-4568 and placebo-treated EDB muscles
次要结局
- Number of Participants With Restoration of Dystrophin Protein Expression Measured by Immunocytochemistry(Day 14 to Day 28)
- Number of Participants With Induced Skipping of Exon 51 in the Treated Extensor Digitorum Brevis (EDB) Muscle Determined by Reverse Transcription Polymerase Chain Reaction(Day 14 to Day 28)
- Number of Participants With Restoration of Dystrophin Protein Expression Measured by Western Blot Analysis(Day 14 to Day 28)